rs41288981

Variant names:

• chr6-137204389-G-A
• rs41288981
• NM_000416.3:c.489C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-137204389-G-A
• chr6-137204389-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000416.3(IFNGR1):​c.489C>T​(p.Pro163Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,613,648 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (75 hom.)
• Consequence: IFNGR1 NM_000416.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.593
• Publications: 4 publications found

Genes affected

IFNGR1 (HGNC:5439): (interferon gamma receptor 1) This gene (IFNGR1) encodes the ligand-binding chain (alpha) of the gamma interferon receptor. Human interferon-gamma receptor is a heterodimer of IFNGR1 and IFNGR2. A genetic variation in IFNGR1 is associated with susceptibility to Helicobacter pylori infection. In addition, defects in IFNGR1 are a cause of mendelian susceptibility to mycobacterial disease, also known as familial disseminated atypical mycobacterial infection. [provided by RefSeq, Jul 2008]

IFNGR1 Gene-Disease associations (from GenCC):

• autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• immunodeficiency 27A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-137204389-G-A is Benign according to our data. Variant chr6-137204389-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.593 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00639 (973/152202) while in subpopulation NFE AF = 0.00975 (663/68010). AF 95% confidence interval is 0.00913. There are 3 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000416.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	NM_000416.3	MANE Select	c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 7	NP_000407.1	A0A0S2Z3Y2
	IFNGR1	NM_001363526.1		c.459C>T	p.Pro153Pro	synonymous	Exon 5 of 8	NP_001350455.1	A0A2R8Y4U4
	IFNGR1	NM_001363527.1		c.366C>T	p.Pro122Pro	synonymous	Exon 4 of 7	NP_001350456.1	A0A2R8YFL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNGR1	ENST00000367739.9	TSL:1 MANE Select	c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 7	ENSP00000356713.5	P15260-1
	IFNGR1	ENST00000957752.1		c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 7	ENSP00000627811.1
	IFNGR1	ENST00000414770.6	TSL:3	c.459C>T	p.Pro153Pro	synonymous	Exon 5 of 8	ENSP00000394230.2	A0A2R8Y4U4

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 975 AN: 152084 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00975

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00631 AC: 1587 AN: 251366 AF XY: 0.00645

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.00933

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00837 AC: 12229 AN: 1461446 Hom.: 75 Cov.: 31 AF XY: 0.00813 AC XY: 5914 AN XY: 727044

African (AFR) AF: 0.00105 AC: 35 AN: 33470

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86250

European-Finnish (FIN) AF: 0.0203 AC: 1082 AN: 53414

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5762

European-Non Finnish (NFE) AF: 0.00950 AC: 10563 AN: 1111656

Other (OTH) AF: 0.00729 AC: 440 AN: 60376

GnomAD4 genome AF: 0.00639 AC: 973 AN: 152202 Hom.: 3 Cov.: 32 AF XY: 0.00648 AC XY: 482 AN XY: 74424

African (AFR) AF: 0.00128 AC: 53 AN: 41514

American (AMR) AF: 0.00183 AC: 28 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0204 AC: 216 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00975 AC: 663 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00884 Hom.: 7

Bravo AF: 0.00482

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00871

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Disseminated atypical mycobacterial infection (1)
-	-	1	Immunodeficiency 27A (1)
-	-	1	Interferon gamma receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.56
DANN	Benign	0.44
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41288981; hg19: chr6-137525526;